Modification of the Tumor Microenvironment in KRAS or c-MYC-Induced Ovarian Cancer-Associated Peritonitis.

• Main Authors: Mitsuyo Yoshida, Ayumi Taguchi, Kei Kawana, Katsuyuki Adachi, Akira Kawata, Juri Ogishima, Hiroe Nakamura, Asaha Fujimoto, Masakazu Sato, Tomoko Inoue, Haruka Nishida, Hitomi Furuya, Kensuke Tomio, Takahide Arimoto, Kaori Koga, Osamu Wada-Hiraike, Katsutoshi Oda, Takeshi Nagamatsu, Tohru Kiyono, Yutaka Osuga, Tomoyuki Fujii
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2016-01-01
• Series: PLoS ONE
• Online Access: http://europepmc.org/articles/PMC4970724?pdf=render

The most common properties of oncogenes are cell proliferation and the prevention of apoptosis in malignant cells, which, as a consequence, induce tumor formation and dissemination. However, the effects of oncogenes on the tumor microenvironment (TME) have not yet been examined in detail. The accumulation of ascites accompanied by chronic inflammation and elevated concentrations of VEGF is a hallmark of the progression of ovarian cancer. We herein demonstrated the mechanisms by which oncogenes contribute to modulating the ovarian cancer microenvironment. c-MYC and KRAS were transduced into the mouse ovarian cancer cell line ID8. ID8, ID8-c-MYC, or ID8-KRAS cells were then injected into the peritoneal cavities of C57/BL6 mice and the production of ascites was assessed. ID8-c-MYC and ID8-KRAS both markedly accelerated ovarian cancer progression in vivo, whereas no significant differences were observed in proliferative activity in vitro. ID8-KRAS in particular induced the production of ascites, which accumulated between approximately two to three weeks after the injection, more rapidly than ID8 and ID8-c-MYC (between nine and ten weeks and between six and seven weeks, respectively). VEGF concentrations in ascites significantly increased in c-MYC-induced ovarian cancer, whereas the concentrations of inflammatory cytokines in ascites were significantly high in KRAS-induced ovarian cancer and were accompanied by an increased number of neutrophils in ascites. A cytokine array revealed that KRAS markedly induced the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in ID8 cells. These results suggest that oncogenes promote cancer progression by modulating the TME in favor of cancer progression.